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Wajid Syed Snr,1 Adel Bashatah,2 Mahmood Basil A Al-Rawi3 1Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia; 2Department of Nursing Administration & Education, College of Nursing, King Saud University, Riyadh, 11451, Saudi Arabia; 3Department of Optometry, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi ArabiaCorrespondence: Wajid Syed Snr, Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia, Tel +966503754169, Email wali@ksu.edu.saBackground and Objective: The role of pharmacists in society is unique since they are providers of drug information and medication counseling to patients. Hence, the present study was designed to investigate the knowledge, of undergraduate pharmacy students regarding food drug (FDIs) and alcohol–drug interactions (ADIs) at King Saud University, Riyadh Saudi Arabia.Methodology: An online cross-sectional study was conducted among undergraduate pharmacy students at King Saud University, Riyadh, Saudi Arabia from October 2021 to January 2022, using self-administered 24-items questionnaires focused on evaluating the knowledge of FDIs and ADIs.Results: Of the 200 questionnaires distributed, 142 students responded, of whom 40.8% (n = 58) of the students did not agree with the statement that patients can eat more green leafy vegetables with warfarin. Just over half 52.8% (n = 75) agreed that milk affects the efficacy of tetracycline. Regarding the students’ knowledge about amiodarone interactions with grapefruit 43% (n = 61) of them were knowledgeable, while 43.7% (n = 62), knew that atorvastatin cannot be taken with grapefruit. A total of 44.4% (n = 63) of the students reported being knowledgeable about FDIs. In terms of the individual questions, Alcohol interactions with antihistamines and paracetamol received the highest percentages of 52.8% (n = 75) and 50.7% (n = 72), respectively, followed by warfarin and methotrexate (45.1%; 41.5%). In this study, 39.4% (n = 56) of the participants were found knowledgeable about ADIs. The overall knowledge of interactions among the students was 47.9% (n = 68). The total knowledgeable levels were significantly associated with educational levels and having previous information about interaction (p = 0.0001).Conclusion: In conclusion, undergraduate pharmacy students exhibited poor knowledge of FDIs and ADIs. As a result, more focus and effort should be given to raising awareness of potential FDIs and ADIs. Our study highlights the need for improving pharmacy students’ knowledge about FDIs and ADIs.Keywords: knowledge, students, interactions, alcohol, food, drugs

The present study aims to explore the potential of a plasma-membrane localized PIP2-type aquaporin protein sourced from the halophyte Salicornia brachiata to alleviate salinity and water deficit stress tolerance in a model plant through transgenic intervention. Transgenic plants overexpressing SbPIP2 gene showed improved physio-biochemical parameters like increased osmolytes (proline, total sugar, and amino acids), antioxidants (polyphenols), pigments and membrane stability under salinity and drought stresses compared to control plants [wild type (WT) and vector control (VC) plants]. Multivariate statistical analysis showed that, under water and salinity stresses, osmolytes, antioxidants and pigments were correlated with SbPIP2-overexpressing (SbPIP2-OE) plants treated with salinity and water deficit stress, suggesting their involvement in stress tolerance. As aquaporins are also involved in CO 2 transport, SbPIP2-OE plants showed enhanced photosynthesis performance than wild type upon salinity and drought stresses. Photosynthetic gas exchange (net CO 2 assimilation rate, PSII efficiency, ETR, and non-photochemical quenching) were significantly higher in SbPIP2-OE plants compared to control plants (wild type and vector control plants) under both unstressed and stressed conditions. The higher quantum yield for reduction of end electron acceptors at the PSI acceptor side [Φ ( R0 ) ] in SbPIP2-OE plants compared to control plants under abiotic stresses indicates a continued PSI functioning, leading to retained electron transport rate, higher carbon assimilation, and less ROS-mediated injuries. In conclusion, the SbPIP2 gene functionally validated in the present study could be a potential candidate for engineering abiotic stress resilience in important crops., (© 2024 Scandinavian Plant Physiology Society.)

Graft versus host disease (GVHD) remains the major cause of morbidity and mortality after allogeneic stem cell transplantation, especially for intestinal GVHD, as steroid resistant GVHD results in high mortality. For this reason, new treatments of GVHD are needed. One approach is the reduction of pathogenic bacteria using anti- E. coli Immunoglobulin Yolk (IgY). In a haploidentical murine model, B6D2F1 mice conditioned with total body irradiation (TBI), received bone marrow cells (BM) and splenocytes (SC) from either syngeneic (Syn = B6D2F1) or allogeneic (Allo = C57BL/6) donors. Following this, animals received from day -2 until day +28 chow contained IgY or control chow. Thereafter the incidence and severity of aGVHD, the cytokines, chemokines, IDO1 and different pathogen-recognition receptors (PRR) were analyzed and compared to control animals (received chow without IgY). We found that animals receiving chow with IgY antibody showed reduced GVHD severity compared to control animals. On day28 after alloBMT, IDO, NOD2, TLR2, TLR4 and the inflammatory chemokine CCL3, were reduced in the colon and correlated with a significant decrease in E. coli bacteria. In summary chow containing chicken antibodies (IgY) improved GVHD via decrease in bacterial load of E coli conducting to reduction of pathogen receptors (NOD2, TLR2 and 4), IDO, chemokines and cytokines., Competing Interests: 7The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

MicroRNAs have been projected as promising tools for diagnostic and prognostic purposes in cancer. More recently, they have been highlighted as RNA therapeutic targets for cancer therapy. Though miRs perform a generic function of post-transcriptional gene regulation, their utility in RNA therapeutics mostly relies on their biochemical nature and their assembly with other macromolecules. Release of extracellular miRs is broadly categorized into two different compositions, namely exosomal (extracellular vesicles) and non-exosomal. This nature of miRs not only affects the uptake into target cells but also poses a challenge and opportunity for RNA therapeutics in cancer. By virtue of their ability to act as mediators of intercellular communication in the tumor microenvironment, extracellular miRs perform both, depending upon the target cell and target landscape, pro- and anti-tumor functions. Tumor-derived miRs mostly perform pro-tumor functions, whereas host cell- or stroma-derived miRs are involved in anti-tumor activities. This review deals with the recent understanding of exosomal and non-exosomal miRs in the tumor microenvironment, as a tool for pro- and anti-tumor activity and prospective exploit options for cancer therapy.

Macrophages constitute a major part of the tumor-infiltrating immune cells. Within the tumor microenvironment, they acquire an alternatively activated, tumor-supporting phenotype. Factors released by tumor cells are crucial for the recruitment of tumor-associated macrophages. In the present project, we aimed to understand the role of hsa-miR-200c-3p (miR-200c) in the interplay between tumor cells and macrophages. To this end, we employed a coculture system of MCF7 breast tumor cells and primary human macrophages and observed the transfer of miR-200c from apoptotic tumor cells to macrophages, which required intact CD36 receptor in macrophages. We further comprehensively determined miR-200c targets in macrophages by mRNA-sequencing and identified numerous migration-associated mRNAs to be downregulated by miR-200c. Consequently, miR-200c attenuated macrophage infiltration into 3-dimensional tumor spheroids. miR-200c-mediated reduction in infiltration further correlated with a miR-200c migration signature comprised of the four miR-200c-repressed, predicted targets PPM1F, RAB11FIB2, RDX, and MSN.

Background : Glucose metabolism in the tumor-microenvironment is a fundamental hallmark for tumor growth and intervention therein remains an attractive option for anti-tumor therapy. Whether tumor-derived factors such as microRNAs (miRs) regulate glucose metabolism in stromal cells, especially in tumor-associated macrophages (TAMs), to hijack them for trophic support, remains elusive. Methods : Ago-RIP-Seq identified macrophage lactate dehydrogenase B (LDHB) as a target of tumor-derived miR-375 in both 2D/3D cocultures and in murine TAMs from a xenograft mouse model. The prognostic value was analyzed by ISH and multiplex IHC of breast cancer patient tissues. Functional consequences of the miR-375-LDHB axis in TAMs were investigated upon mimic/antagomir treatment by live metabolic flux assays, GC/MS, qPCR, Western blot, lentiviral knockdown and FACS. The therapeutic potential of a combinatorial miR-375-decoy/simvastatin treatment was validated by live cell imaging. Results : Macrophage LDHB decreased in murine and human breast carcinoma. LDHB downregulation increase aerobic glycolysis and lactagenesis in TAMs in response to tumor-derived miR-375. Lactagenesis reduced fatty acid synthesis but activated SREBP2, which enhanced cholesterol biosynthesis in macrophages. LDHB downregulation skewed TAMs to function as a lactate and sterol/oxysterol source for the proliferation of tumor cells. Restoring of LDHB expression potentiated inhibitory effects of simvastatin on tumor cell proliferation. Conclusion : Our findings identified a crucial role of LDHB in macrophages and established tumor-derived miR-375 as a novel regulator of macrophage metabolism in breast cancer, which might pave the way for strategies of combinatorial cancer cell/stroma cell interventions., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The tumor-microenvironment (TME) is an amalgamation of various factors derived from malignant cells and infiltrating host cells, including cells of the immune system. One of the important factors of the TME is microRNAs (miRs) that regulate target gene expression at a post transcriptional level. MiRs have been found to be dysregulated in tumor as well as in stromal cells and they emerged as important regulators of tumorigenesis. In fact, miRs regulate almost all hallmarks of cancer, thus making them attractive tools and targets for novel anti-tumoral treatment strategies. Tumor to stroma cell cross-propagation of miRs to regulate protumoral functions has been a salient feature of the TME. MiRs can either act as tumor suppressors or oncogenes (oncomiRs) and both miR mimics as well as miR inhibitors (antimiRs) have been used in preclinical trials to alter cancer and stromal cell phenotypes. Owing to their cascading ability to regulate upstream target genes and their chemical nature, which allows specific pharmacological targeting, miRs are attractive targets for anti-tumor therapy. In this review, we cover a recent update on our understanding of dysregulated miRs in the TME and provide an overview of how these miRs are involved in current cancer-therapeutic approaches from bench to bedside.

Recent studies suggested an important contribution of sphingosine-1-phospate (S1P) signaling via its specific receptors (S1PRs) in the production of pro-inflammatory mediators such as Interleukin (IL)-1β in cancer and inflammation. In an inflammation-driven cancer setting, we previously reported that myeloid S1PR1 signaling induces IL-1β production by enhancing NLRP3 (NOD-, LRR- and Pyrin Domain-Containing Protein 3) inflammasome activity. However, the autocrine role of S1P and enzymes acting on the S1P rheostat in myeloid cells are unknown. Using human and mouse macrophages with pharmacological or genetic intervention we explored the relative contribution of sphingosine kinases (SPHKs) in NLRP3 inflammasome activity regulation. We noticed redundancy in SPHK1 and SPHK2 activities towards macrophage NLRP3 inflammasome transcriptional induction and IL-1β secretion. However, pharmacological blockade of both kinases in unison completely abrogated NLRP3 inflammasome induction and IL-1β secretion. Interestingly, human and mouse macrophages demonstrate varied responses towards SPHKs inhibition and IL-1β secretion. Clinical datasets of renal cell carcinoma and psoriasis patients showed a positive correlation between enzymes affecting the S1P rheostat with NLRP3 inflammasome components expression, which corroborates our finding. Our data provide a better understanding on the role of SPHKs and de novo synthesized S1P in macrophage NLRP3 inflammasome activation.

A myriad of signaling molecules in a heuristic network of the tumor microenvironment (TME) pose a challenge and an opportunity for novel therapeutic target identification in human cancers. MicroRNAs (miRs), due to their ability to affect signaling pathways at various levels, take a prominent space in the quest of novel cancer therapeutics. The role of miRs in cancer initiation, progression, as well as in chemoresistance, is being increasingly investigated. The canonical function of miRs is to target mRNAs for post-transcriptional gene silencing, which has a great implication in first-order regulation of signaling pathways. However, several reports suggest that miRs also perform non-canonical functions, partly due to their characteristic non-coding small RNA nature. Examples emerge when they act as ligands for toll-like receptors or perform second-order functions, e.g., to regulate protein translation and interactions. This review is a compendium of recent advancements in understanding the role of miRs in cancer signaling and focuses on the role of miRs as novel regulators of the signaling pathway in the TME.

MicroRNAs (miRs) significantly contribute to the regulation of gene expression, by virtue of their ability to interact with a broad, yet specific set of target genes. MiRs are produced and released by almost every cell type and play an important role in horizontal gene regulation in the tumor microenvironment (TME). In the TME, both tumor and stroma cells cross-communicate via diverse factors including miRs, which are taking central stage as a therapeutic target of anti-tumor therapy. One of the immune escape strategies adopted by tumor cells is to release miRs as a Trojan horse to hijack circulating or tumor-localized monocytes/macrophages to tune them for pro-tumoral functions. On the other hand, macrophage-derived miRs exert anti-tumor functions. The transfer of miRs from host to recipient cells depends on the supramolecular structure and composition of miR carriers, which determine the distinct uptake mechanism by recipient cells. In this review, we provide a recent update on the miR-mediated crosstalk between tumor cells and macrophages and their mode of uptake in the TME., Competing Interests: The authors declare no conflict of interest.

The bioactive lipid sphingosine-1-phosphate (S1P), along with its receptors, modulates lymphocyte trafficking and immune responses to regulate skin inflammation. Macrophages are important in the pathogenesis of psoriasiform skin inflammation and express various S1P receptors. How they respond to S1P in skin inflammation remains unknown. We show that myeloid specific S1P receptor 1 (S1PR1) deletion enhances early inflammation in a mouse model of imiquimod-induced psoriasis, without altering the immune cell infiltrate. Mechanistically, myeloid S1PR1 deletion altered the formation of IL-1β, VEGF-A, and VEGF-C, and their receptors' expression in psoriatic skin, which subsequently lead to reciprocal regulation of neoangiogenesis and neolymphangiogenesis. Experimental findings were corroborated in human clinical datasets and in knockout macrophages in vitro. Increased blood vessel but reduced lymph vessel density may explain the exacerbated inflammatory phenotype in conditional knockout mice. These findings assign a novel role to macrophage S1PR1 and provide a rationale for therapeutically targeting local S1P during skin inflammation.

Cytotoxic T lymphocyte (CTL) activation contributes to liver damage during sepsis, but the mechanisms involved are largely unknown. Understanding the underlying principle will permit interference with CTL activation and thus, provide a new therapeutic option. Methods: To elucidate the mechanism leading to CTL activation we used the Hepa1-6 cell line in vitro and the mouse model of in vivo polymicrobial sepsis, following cecal-ligation and -puncture (CLP) in wildtype, myeloid specific NOX-2, global NOX2 and NOX4 knockout mice, and their survival as a final readout. In this in vivo setting, we also determined hepatic mRNA and protein expression as well as clinical parameters of liver damage - aspartate- and alanine amino-transaminases. Hepatocyte specific overexpression of PD-L1 was achieved in vivo by adenoviral infection and transposon-based gene transfer using hydrodynamic injection. Results: We observed downregulation of PD-L1 on hepatocytes in the murine sepsis model. Adenoviral and transposon-based gene transfer to restore PD-L1 expression, significantly improved survival and reduced the release of liver damage, as PD-L1 is a co-receptor that negatively regulates T cell function. Similar protection was observed during pharmacological intervention using recombinant PD-L1-Fc. N-acetylcysteine blocked the downregulation of PD-L1 suggesting the involvement of reactive oxygen species. This was confirmed in vivo, as we observed significant upregulation of PD-L1 expression in NOX4 knockout mice, following sham operation, whereas its expression in global as well as myeloid lineage NOX2 knockout mice was comparable to that in the wild type animals. PD-L1 expression remained high following CLP only in total NOX2 knockouts, resulting in significantly reduced release of liver damage markers. Conclusion: These results suggest that, contrary to common assumption, maintaining PD-L1 expression on hepatocytes improves liver damage and survival of mice during sepsis. We conclude that administering recombinant PD-L1 or inhibiting NOX2 activity might offer a new therapeutic option in sepsis., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Tumor-immune cell interactions shape the immune cell phenotype, with microRNAs (miRs) being crucial components of this crosstalk. How they are transferred and how they affect their target landscape, especially in tumor-associated macrophages (TAMs), is largely unknown. Here we report that breast cancer cells have a high constitutive expression of miR-375, which is released as a non-exosome entity during apoptosis. Deep sequencing of the miRome pointed to enhanced accumulation of miR-375 in TAMs, facilitated by the uptake of tumor-derived miR-375 via CD36. In macrophages, miR-375 directly targets TNS3 and PXN to enhance macrophage migration and infiltration into tumor spheroids and in tumors of a xenograft mouse model. In tumor cells, miR-375 regulates CCL2 expression to increase recruitment of macrophages. Our study provides evidence for miR transfer from tumor cells to TAMs and identifies miR-375 as a crucial regulator of phagocyte infiltration and the subsequent development of a tumor-promoting microenvironment.

Macrophages in the tumor microenvironment respond to complex cytokine signals. How these responses shape the phenotype of tumor-associated macrophages (TAMs) is incompletely understood. Here we explored how cytokines of the tumor milieu, interleukin (IL)-6 and IL-4, interact to influence target gene expression in primary human monocyte-derived macrophages (hMDMs). We show that dual stimulation with IL-4 and IL-6 synergistically modified gene expression. Among the synergistically induced genes are several targets with known pro-tumorigenic properties, such as CC-chemokine ligand 18 (CCL18), transforming growth factor alpha (TGFA) or CD274 (programmed cell death 1 ligand 1 (PD-L1)). We found that transcription factors of the signal transducer and activator of transcription (STAT) family, STAT3 and STAT6 bind regulatory regions of synergistically induced genes in close vicinity. STAT3 and STAT6 co-binding further induces the basic leucine zipper ATF-like transcription factor (BATF), which participates in synergistic induction of target gene expression. Functional analyses revealed increased MCF-7 and MDA-MB 231 tumor cell motility in response to conditioned media from co-treated hMDMs compared to cells incubated with media from single cytokine-treated hMDMs. Flow cytometric analysis of T cell populations upon co-culture with hMDMs polarized by different cytokines indicated that dual stimulation promoted immunosuppressive properties of hMDMs in a PD-L1-dependent manner. Analysis of clinical data revealed increased expression of BATF together with TAM markers in tumor stroma of breast cancer patients as compared to normal breast tissue stroma. Collectively, our findings suggest that IL-4 and IL-6 cooperate to alter the human macrophage transcriptome, endowing hMDMs with pro-tumorigenic properties.

IgG Fc receptors (FcγRs) and the C5a anaphylatoxin receptor (C5aR) were identified as key regulators of type II autoimmune injury in mice. However, and with respect to C5aR, the relative importance of C5a for IgG autoantibody-induced cellular destruction remained unclear. Using an experimental model of autoimmune hemolytic anemia (AIHA), we here report marked differences in the development of AIHA between mice lacking C5aR and C5-deficient (Hc 0 ) strain, indicating a limited role of C5 in this type of C5aR-regulated disease. Ex-vivo-analyses of liver homogenates from anemic Hc 0 mice demonstrate C5a-independent C5aR activation, upregulation of FcγR expression and amplification of erythrophagocytosis by macrophages. As assessed by pharmacological inhibition studies, targeting of C5aR, but not of C5, is effective in treating experimental AIHA. Collectively, these results define a previously unrecognized disease mechanism of C5aR activation in AIHA that does not necessarily involve C5 and C5a., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Store-operated calcium entry (SOCE) is the most common mode of calcium influx in non-excitable cells, including immune cells. The two STIM isoforms mediate SOCE as well as Fc receptor (FcR)-downstream activation of macrophages and mast cells-which appears to be relevant in vivo, in models of antibody-dependent tissue injury and allergy. Hence, the pathway of SOCE may be a therapeutic target for treatment of immune complex (IC)-mediated autoimmunity and allergic asthma. The pyrazole derivative, BTP2 is an efficient inhibitor of SOCE, which has already been shown to attenuate allergic inflammation. However, its effect on Fc gamma receptor (FcγR) signaling and IC-induced tissue injury had not yet been studied. Here, we show that BTP2 is a potent inhibitor of SOCE in primary macrophages, blocking FcγR-mediated responses. To investigate the effect of inhibition of SOCE in IC-mediated tissue injury, we induced reverse passive Arthus reaction to IgG immune complexes in the skin and lungs of BTP2- or control-treated mice. Treatment with BTP2 resulted in markedly attenuated inflammation in both the skin and the lungs. Our findings indicate the involvement of SOCE in FcγR-mediated responses in vitro and in vivo and suggest that BTP2-mediated inhibition of SOCE may have a therapeutic potential on IC-mediated autoimmunity.

Metastasis is the primary cause of cancer death. The inflammatory tumor microenvironment contributes to metastasis, for instance, by recruiting blood and lymph vessels. Among tumor-infiltrating immune cells, tumor-associated macrophages (TAMs) take a center stage in promoting both tumor angiogenesis and metastatic spread. We found that genetic deletion of the S1P receptor 1 ( S1pr1 ) alone in CD11b hi CD206 + TAMs infiltrating mouse breast tumors prevents pulmonary metastasis and tumor lymphangiogenesis. Reduced lymphangiogenesis was also observed in the nonrelated methylcholanthrene-induced fibrosarcoma model. Transcriptome analysis of isolated TAMs from both entities revealed reduced expression of the inflammasome component Nlrp3 in S1PR1-deficient TAMs. Macrophage-dependent lymphangiogenesis in vitro was triggered upon inflammasome activation and required both S1PR1 signaling and IL-1β production. Finally, NLRP3 expression in tumor-infiltrating macrophages correlated with survival, lymph node invasion, and metastasis of mammary carcinoma patients. Conceptually, our study indicates an unappreciated role of the NLRP3 inflammasome in promoting metastasis via the lymphatics downstream of S1PR1 signaling in macrophages., (© 2017 Weichand et al.)

Significance: Leukocytes and especially macrophages are a major cellular constituent of the tumor mass. The tumor microenvironment not only determines their activity but in turn these cells also contribute to tumor initiation and progression. Recent Advances: Proinflammatory stimulated macrophages upregulate inducible nitric oxide synthase (NOS2) and produce high steady-state NO concentrations. NO provokes tumor cell death by initiating apoptosis and/or necrosis. Mechanisms may comprise p53 accumulation, immunestimulatory activities, and an increased efficacy of chemo- and/or radiotherapy. However, the potential cytotoxic activity of macrophages often is compromised in the tumor microenvironment and instead a protumor activity of macrophages dominates. Contributing factors are signals generated by viable and dying tumor cells, attraction and activation of myeloid-derived suppressor cells, and hypoxia. Limited oxygen availability not only attenuates NOS2 activity but also causes accumulation of hypoxia-inducible factors 1 and 2 (HIF-1/HIF-2). Activation of the HIF system is tightly linked to NO formation and affects the expression of macrophage phenotype markers that in turn add to tumor progression., Critical Issues: To make use of the cytotoxic arsenal of activated macrophages directed against tumor cells, it will be critical to understand how, when, and where these innate immune responses are blocked and whether it will be possible to reinstall their full capacity to kill tumor cells., Future Directions: Low-dose irradiation or proinflammatory activation of macrophages in the tumor microenvironment may open options to boost NOS2 expression and activity and to initiate immunestimulatory features of NO that may help to restrict tumor growth. Antioxid. Redox Signal. 26, 1023-1043.

Objective: In this study, we evaluated anti-inflammatory activity of leaves of Fumaria parviflora ( F. parviflora ) and underlying mechanisms by using in vivo models of inflammation., Material and Methods: Albino Wistar rats of either sex weighing 150 - 200 g were used. Soxhlet ethanol and aqueous extracts of leaves of F. parviflora (EFP and AFP) were prepared. The anti-inflammatory activity was studied using carrageenan-induced paw edema method and cotton pellet granuloma method. Levels of cytokines such as TNF-α, IL-6 and IL-1 and activity of antioxidant enzymes including catalase (CAT) and glutathione peroxidase (GPx) were estimated., Results: Leaves of F. parviflora demonstrated significant (p<0.001) decrease in paw edema in carrageenan-induced paw edema method. It diminished the serum tumour necrosis factor-α (TNF-α), IL-6 and IL-1 levels and also significantly attenuated the malondialdehyde (MDA) levels. The activity of CAT and GPx was increased in paw tissue. It also demonstrated significant decrease in granuloma formation in cotton pellet-induced granuloma method., Conclusion: Leaves of F. parviflora possess anti-inflammatory activity as they inhibit various cytokines and have antioxidant effects and free radical scavenging activity.

A pleiotropic signaling lipid, sphingosine-1-phosphate (S1P), has been implicated in various pathophysiological processes supporting tumor growth and metastasis. However, there are only a few descriptive studies suggesting a role of S1P in tumor lymphangiogenesis, which is critical for tumor growth and dissemination. Corroborating own data, the literature suggests that apoptotic tumor cell-derived S1P alters the phenotype of tumor-associated macrophages (TAMs) to gain protumor functions. However, mechanistically, the role of TAM-induced lymphangiogenesis has only been poorly described, mostly linked to the production of lymphangiogenic factors such as vascular endothelial growth factor C (VEGF-C) and VEGF-D, or transdifferentiation into lymphatic endothelial cells. Recent findings highlight a rather underappreciated role of S1P in tumor lymphangiogenesis, referring to the production of interleukin-1 β (IL-1 β ) and lipocalin-2 (LCN2) by a tumor-promoting macrophage phenotype. In this review, we aim to provide to the readers with the current understanding of the molecular mechanism how apoptotic cell-derived S1P triggers TAMs to promote lymphangiogenesis.

Polyhydroxyalkanoate (PHA) biopolymers are widely recognised as outstanding candidates to replace conventional petroleum-derived polymers. Their mechanical properties are good and can be tailored through copolymer composition, they are biodegradable, and unlike many alternatives, they do not rely on oil-based feedstocks. Further, they are the only commodity polymer that can be synthesised intracellularly, ensuring stereoregularity and high molecular weight. However, despite offering enormous potential for many years, they are still not making a significant impact. This is broadly because commercial uptake has been limited by variable performance (inconsistent polymer properties) and high production costs of the raw polymer. Additionally, the main type of PHA produced naturally is poly-3-hydroxybutyrate (PHB), which has limited scope due to its brittle nature and low thermal stability, as well as its tendency to embrittle over time. Production cost is strongly impacted by the type of the feedstock used. In this article we consider: the production of PHAs from methanotrophs using methane as a cost-effective substrate; the use of mixed cultures, as opposed to pure strains; and strategies to generate a poly(3-hydroxybutyrate-co-3-hydroxyvalerate) copolymer (PHBV), which has more desirable qualities such as toughness and elasticity., Competing Interests: The authors declare no conflict of interest.

Calcium (Ca(2+)) signaling in immune cells, including macrophages, controls a wide range of effector functions that are critical for host defense and contribute to inflammation and autoimmune diseases. However, receptor-mediated Ca(2+) responses consist of complex mechanisms that make it difficult to identify the pathogenesis and develop therapy. Previous studies have revealed the importance of the Ca(2+) sensor STIM1 and store-operated Ca(2+)-entry (SOCE) for Fcγ-receptor activation and IgG-induced inflammation. Here, we identify the closely related STIM2 as mediator of cell migration and cytokine production downstream of GPCR and TLR4 activation in macrophages and show that mice lacking STIM2 are partially resistant to inflammatory responses in peritonitis and LPS-induced inflammation. Interestingly, STIM2 modulates the migratory behavior of macrophages independent from STIM1 and without a strict requirement for Ca(2+) influx. While STIM2 also contributes in part to FcγR activation, the C5a-induced amplification of IgG-mediated phagocytosis is mainly dependent on STIM1. Blockade of STIM-related functions limits mortality in experimental models of AIHA and LPS-sepsis in normal mice. These results suggest benefits of Ca(2+)-inhibition for suppression of exacerbated immune reactions and illustrate the significance of alternate functions of STIM proteins in macrophage activation and in the context of innate immune inflammation.

Urban environmental quality is vital to be investigated as the majority of people live in cities. However, given the continuous urbanization and industrialization in urban areas, heavy metals are continuously emitted into the terrestrial environment and pose a great threat to human. In this study, a total of 76 urban surface soil samples were collected in the Klang district (Malaysia), and analyzed for total and bioavailable heavy metal concentrations by inductively coupled plasma-optical emission spectrometry. Results showed that the concentrations of bioavailable heavy metals declined in the order of Al, Fe, Zn, Cu, Co, Cd, Pb, and Cr, and the concentrations of total heavy metals declined in the order of Fe, Al, Cu, Zn, Pb, Cr, Co, and Cd. Principal component analysis (PCA) showed that heavy metals could be grouped into three principal components, with PC1 containing Al and Fe, PC2 comprising Cd, Co, Cr, and Cu, and PC3 with only Zn. PCA results showed that PC1 may originate from natural sources, whereas PC2 and PC3 most likely originated from anthropogenic sources. Health risk assessment indicated that heavy metal contamination in the Klang district was below the acceptable threshold for carcinogenic and non-carcinogenic risks in adults, but above the acceptable threshold for carcinogenic and non-carcinogenic risks in children.

Bleached kenaf core pulps (BKC) were hydrolyzed in H2SO4 (0.5M) at different time (0min to 90min) at room temperature. After the hydrolysis process, the viscosity average molecular weight (Mŋ) for BKC sample has reduced from 14.5×10(4) to 2.55×10(4). The hydrolyzed BKC was then dissolved in NaOH:urea:water and in LiOH:urea:water mixed solvent at the ratio of 7:12:81 and 4.6:15:80.4, respectively. The increased in hydrolysis time has decreased Mŋ of cellulose leading to easy dissolution process. Higher porosity and transparency with lower crystallinity index (CrI) of regenerated membrane produced can be achieved as the Mŋ reduced. The properties of membrane were observed through FESEM, UV-vis spectrophotometer and XRD. This study has proven that acid hydrolysis has reduced the Mŋ of cellulose, thus, enhanced the properties of regenerated membrane produced with assisted by alkaline/urea system., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Basophils are known to modulate the phenotype of CD4(+) T cells and to enhance T helper type 2 responses in vitro and in vivo. In this study, we demonstrate that murine basophils inhibit proliferation of CD4(+) T cells in autologous and allogeneic mixed lymphocyte reactions. The inhibition is independent of Fas and MHC class II, but dependent on activation of basophils with subsequent release of interleukin-4 (IL-4) and IL-6. The inhibitory effect of basophils on T-cell proliferation can be blocked with antibodies against IL-4 and IL-6 and is absent in IL-4/IL-6 double-deficient mice. In addition, we show that basophils and IL-4 have beneficial effects on disease activity in a murine model of acute graft-versus-host disease (GvHD). When basophils were depleted with the antibody MAR-1 before induction of GvHD, weight loss, GvHD score, mortality and plasma tumour necrosis factor levels were increased while injection of IL-4 improved GvHD. Basophil-depleted mice with GvHD also have increased numbers of CD4(+) T cells in the mesenteric lymph nodes. Our data show for the first time that basophils suppress autologous and allogeneic CD4(+) T-cell proliferation in an IL-4-dependent manner., (© 2014 John Wiley & Sons Ltd.)

Objective: To identify the relationship between knowledge, attitude and perception regarding environmental tobacco smoke (ETS) and smoking among Malaysian adolescents living in states with complete or partial smoke-free legislation (SFL)., Methods: A total of 898 respondents aged 13-14 years were randomly selected from 21 secondary schools. The Malay version of the modified Global Youth Tobacco Survey questionnaire was used. Hierarchical logistic regression was performed in examining predictors of smoking attempt among adolescents., Results: Participants exposed to ETS >5 h/day were more likely to have smoked compared to those exposed to ETS <1 h/day (OR 4.1, 95%CI 1.03-16.0). Living in a state with partial SFL was associated with a two-fold increase in self-reported smoking attempts (OR 1.95, 95%CI 1.10-3.43) compared to living in a state with complete SFL. Negative attitudes and perceptions towards smoking and ETS exposure were linked to lower smoking attempts in states with complete SFL., Conclusions: Adolescents with limited ETS exposure who lived in a state with complete SFL were less likely to attempt smoking compared to those exposed more regularly to ETS and living in a state with partial SFL. Preventing adolescents from becoming smokers is the key to reducing national prevalence rates in smoking. There is a need to implement comprehensive smoke-free legislation nationally across Malaysia.

Background: Percutaneous pins used in the surgical fixation of fractures in children are often removed in the outpatient clinic without the administration of analgesia. Pin removal can be a cause of anxiety for children, parents, and caregivers. Relatively little is known about the requirement of analgesia for this procedure. In a randomized controlled trial, we evaluated whether oral acetaminophen or ibuprofen reduced the pain experienced during pin removal., Methods: Participating in the study were 240 children between the ages of five and twelve years who had two or three percutaneous pins in the elbow following treatment of a supracondylar humeral fracture or a lateral humeral condyle fracture with closed reduction and percutaneous pinning. The patients were randomized into one of three groups (n = 80) allocated to receive acetaminophen, ibuprofen, or vitamin C (placebo) an hour before pin removal. A pain score was obtained and heart rate measured before pin removal, immediately following the procedure, and ten minutes after pin removal., Results: No significant differences were found among the study groups in terms of the demographic data of sex, age, side of injury, or number of pins. Pain score and heart rate did not exhibit differences that were either statistically significant or clinically relevant. The change from baseline did not differ significantly among the groups for either measure at either of the follow-up times post pin removal. Immediately after pin removal, the mean difference in pain score (and 95% confidence interval [CI]) between the acetaminophen group and the ibuprofen group was 0.10 (-1.03 to 1.23); between the acetaminophen group and the placebo group, 0.35 (-0.78 to 1.48); and between the ibuprofen group and the placebo group, 0.25 (-0.88 to 1.38). The CIs excluded a clinically relevant difference. Pain scores and heart rates returned to preprocedural baseline levels within ten minutes following pin removal., Conclusions: Neither acetaminophen nor ibuprofen significantly reduced the pain score or heart rate associated with percutaneous pin removal in children as compared with the placebo. The oral analgesics administered were clinically equivalent to the placebo. These results suggest that non-narcotic analgesia use does not significantly reduce pain or heart rate associated with percutaneous pin removal in children.

Background: Dietary carbohydrate, fiber and sugar intake has been shown to play a role in the etiology of breast cancer, but the findings have been inconsistent and limited to developed countries with higher cancer incidence., Objective: To examine the association of premenopausal and postmenopausal breast cancer risk with dietary carbohydrate, fiber and sugar intake., Materials and Methods: This population based case-control study was conducted in Malaysia with 382 breast cancer patients and 382 controls. Food intake pattern was assessed via an interviewer-administered food frequency questionnaire. Logistic regression was used to compute odds ratios (OR) with 95% confidence intervals (CI) and a broad range of potential confounders were included in analysis., Results: A significant two fold increased risk of breast cancer among premenopausal (OR Q4 to Q1=1.93, 95%CI: 1.53-2.61, p-trend=0.001) and postmenopausal (OR Q4 to Q1=1.87, 95%CI: 1.03-2.61, p-trend=0.045) women was observed in the highest quartile of sugar. A higher intake of dietary fiber was associated with a significantly lower breast cancer risk among both premenopausal (OR Q4 to Q1=0.31, 95%CI: 0.12-0.79, p-trend=0.009) and postmenopausal (OR Q4 to Q1=0.23, 95%CI: 0.07-0.76, p-trend=0.031) women., Conclusions: Sugar and dietary fiber intake were independently related to pre- and postmenopausal breast cancer risk. However, no association was observed for dietary carbohydrate intake.

Basophils have been recognized as important inducers of T helper type 2 (Th2) responses. Using the colitis model of adoptive transfer of CD4(+) CD62L(+) T cells into lymphopenic hosts, we have analyzed how basophils regulate T-cell responses and modulate disease activity. Transferred T cells rapidly proliferate, produce large amounts of interleukin (IL)-3, and expand the number of basophils in an IL-3-dependent manner. Depletion of basophils with two different antibodies substantially upregulated Th1 cytokines in transferred T cells at day 8. Increased Th1 cytokine expression persisted until the end of the experiment when basophil-depleted mice showed exacerbation of colitis with more severe loss of weight, histological damage, colonic leukocyte infiltration, and expression of pro-inflammatory cytokines. In vitro, we show that basophil-derived IL-4 and IL-6 downregulates expression of interferon-γ, IL-2, and tumor necrosis factor in T cells. These data show a beneficial role of basophils in a T-cell driven model of autoimmunity.

This study aims to determine the concentrations of total coliforms and Escherichia coli (E. coli) in beach water, Teluk Kemang beach. This study was also aimed to determine relationship between total coliforms, E. coli and physicochemical parameters. As perceived health symptoms among beach visitors are rarely incorporated in beach water studies, this element was also assessed in this study. A total of eight water sampling points were selected randomly along Teluk Kemang beach. Total coliforms concentrations were found between 20 and 1940 cfu/100ml. E. coli concentrations were between 0 and 90 cfu/100ml. Significant correlations were found between total coliforms and E. coli with pH, temperature and oxidation reduction potential. Skin and eyes symptoms were the highest reported though in small numbers. Microbiological water quality in Teluk Kemang public beach was generally safe for recreational activities except sampling location near with sewage outfall., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objectives: The frequency of common oncogenic mutations and TP53 was determined in Asian oral squamous cell carcinoma (OSCC)., Materials and Methods: The OncoCarta(™) panel v1.0 assay was used to characterize oncogenic mutations. In addition, exons 4-11 of the TP53 gene were sequenced. Statistical analyses were conducted to identify associations between mutations and selected clinico-pathological characteristics and risk habits., Results: Oncogenic mutations were detected in PIK3CA (5.7%) and HRAS (2.4%). Mutations in TP53 were observed in 27.7% (31/112) of the OSCC specimens. Oncogenic mutations were found more frequently in non-smokers (p = 0.049) and TP53 truncating mutations were more common in patients with no risk habits (p = 0.019). Patients with mutations had worse overall survival compared to those with absence of mutations; and patients who harbored DNA binding domain (DBD) and L2/L3/LSH mutations showed a worse survival probability compared to those patients with wild type TP53. The majority of the oncogenic and TP53 mutations were G:C > A:T and A:T > G:C base transitions, regardless of the different risk habits., Conclusion: Hotspot oncogenic mutations which are frequently present in common solid tumors are exceedingly rare in OSCC. Despite differences in risk habit exposure, the mutation frequency of PIK3CA and HRAS in Asian OSCC were similar to that reported in OSCC among Caucasians, whereas TP53 mutations rates were significantly lower. The lack of actionable hotspot mutations argue strongly for the need to comprehensively characterize gene mutations associated with OSCC for the development of new diagnostic and therapeutic tools.

Mucosal inflammation in conditions ranging from infective acute enteritis or colitis to inflammatory bowel disease is accompanied by alteration in serotonin (5-hydroxytryptamine [5-HT]) content in the gut. Recently, we have identified an important role of 5-HT in the pathogenesis of experimental colitis. 5-HT type 7 (5-HT7) receptor is one of the most recently identified members of the 5-HT receptor family, and dendritic cells express this receptor. In this study, we investigated the effect of blocking 5-HT7 receptor signaling in experimental colitis with a view to develop an improved therapeutic strategy in intestinal inflammatory disorders. Colitis was induced with dextran sulfate sodium (DSS) or dinitrobenzene sulfonic acid (DNBS) in mice treated with selective 5-HT7 receptor antagonist SB-269970, as well as in mice lacking 5-HT7 receptor (5-HT7(-/-)) and irradiated wild-type mice reconstituted with bone marrow cells harvested from 5-HT7(-/-) mice. Inhibition of 5-HT7 receptor signaling with SB-269970 ameliorated both acute and chronic colitis induced by DSS. Treatment with SB-269970 resulted in lower clinical disease, histological damage, and proinflammatory cytokine levels compared with vehicle-treated mice post-DSS. Colitis severity was significantly lower in 5-HT7(-/-) mice and in mice reconstituted with bone marrow cells from 5-HT7(-/-) mice compared with control mice after DSS colitis. 5-HT7(-/-) mice also had significantly reduced DNBS-induced colitis. These observations provide us with novel information on the critical role of the 5-HT7 receptor in immune response and inflammation in the gut, and highlight the potential benefit of targeting this receptor to alleviate the severity of intestinal inflammatory disorders such as inflammatory bowel disease.

Hybridization of complementary nucleic acid strands is fundamental to nearly all molecular bioanalytical methods ranging from polymerase chain reaction and DNA biosensors to next generation sequencing. For nucleic acid amplification methods, controlled DNA denaturation and renaturation is particularly essential and achieved by cycling elevated temperatures. Although this is by far the most used technique, the management of rapid temperature changes requires bulky instrumentation and intense power supply. These factors so far precluded the development of true point-of-care tests for molecular diagnostics. To overcome this limitation we explored the possibility of using electrochemical means to control reversible DNA hybridization by using the electroactive intercalator daunomycin (DM). We show that redox-state switching of DM altered its properties from DNA binding to nonbinding, under otherwise constant conditions, and thus altered the thermodynamic stability of duplex DNA. The operational principle was demonstrated using complementary synthetic 20mer and 40mer DNA oligonucleotides. Absorbance-based melting curve analysis revealed significantly higher melting temperatures for DNA in the presence of oxidized compared to chemically reduced DM. This difference was exploited to drive cyclic electrochemically controlled denaturation and renaturation. Analysis with in situ UV-vis and circular dichroism spectroelectrochemistry, as two independent techniques, indicated that up to 80% of the DNA was reversibly hybridized. This remarkable demonstration of electrochemical control of five cycles of DNA denaturation and renaturation, under otherwise constant conditions, could have wide-ranging implications for the future development of miniaturized analytical systems for molecular diagnostics and beyond.

The presence of lymph node (LN) metastasis significantly affects the survival of patients with oral squamous cell carcinoma (OSCC). Successful detection and removal of positive LNs are crucial in the treatment of this disease. Current evaluation methods still have their limitations in detecting the presence of tumor cells in the LNs, where up to a third of clinically diagnosed metastasis-negative (N0) patients actually have metastasis-positive LNs in the neck. We developed a molecular signature in the primary tumor that could predict LN metastasis in OSCC. A total of 211 cores from 55 individuals were included in the study. Eleven proteins were evaluated using immunohistochemical analysis in a tissue microarray. Of the 11 biomarkers evaluated using receiver operating curve analysis, epidermal growth factor receptor (EGFR), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (HER-2/neu), laminin, gamma 2 (LAMC2), and ras homolog family member C (RHOC) were found to be significantly associated with the presence of LN metastasis. Unsupervised hierarchical clustering-demonstrated expression patterns of these 4 proteins could be used to differentiate specimens that have positive LN metastasis from those that are negative for LN metastasis. Collectively, EGFR, HER-2/neu, LAMC2, and RHOC have a specificity of 87.5% and a sensitivity of 70%, with a prognostic accuracy of 83.4% for LN metastasis. We also demonstrated that the LN signature could independently predict disease-specific survival (P = .036). The 4-protein LN signature validated in an independent set of samples strongly suggests that it could reliably distinguish patients with LN metastasis from those who were metastasis-free and therefore could be a prognostic tool for the management of patients with OSCC., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To survey caregivers with regard to the pain they perceived their children were having during the removal of the percutaneous Kirschner wires, as well as the need for analgesia., Methods: 23 male and 18 female patients aged 1 to 15 (mean, 7) years who underwent closed reduction and percutaneous Kirschner wire fixation for elbow fractures and subsequent removal of the wires were included. Before the removal procedure, caregivers of these patients were asked to select one of 4 options for the procedure: no analgesia, paracetamol, sedation, and general anaesthesia. Approximately one month following the procedure, the caregivers were interviewed via telephone to retrospectively score the pain (on a scale of 1 to 10) they perceived their children were having during the removal procedure., Results: The mean retrospective pain score given by these caregivers was 3.88. Of the 41 caregivers, 30 considered analgesia unnecessary, 10 opted for paracetamol, and only one opted for sedation. None considered general anaesthesia necessary., Conclusion: For these children with elbow fractures, most caregivers considered analgesia unnecessary during the removal of percutaneous wires.

Various heterotrimeric G(i) proteins are considered to be involved in cell migration and effector function of immune cells. The underlying mechanisms, how they control the activation of myeloid effector cells, are not well understood. To elucidate isoform-redundant and -specific roles for Gα(i) proteins in these processes, we analyzed mice genetically deficient in Gα(i2) or Gα(i3). First, we show an altered distribution of tissue macrophages and blood monocytes in the absence of Gα(i2) but not Gα(i3). Gα(i2)-deficient but not wild-type or Gα(i3)-deficient mice exhibited reduced recruitment of macrophages in experimental models of thioglycollate-induced peritonitis and LPS-triggered lung injury. In contrast, genetic ablation of Gα(i2) had no effect on Gα(i)-dependent peritoneal cytokine production in vitro and the phagocytosis-promoting function of the Gα(i)-coupled C5a anaphylatoxin receptor by liver macrophages in vivo. Interestingly, actin rearrangement and CCL2- and C5a anaphylatoxin receptor-induced chemotaxis but not macrophage CCR2 and C5a anaphylatoxin receptor expression were reduced in the specific absence of Gα(i2). Furthermore, knockdown of Gα(i2) caused decreased cell migration and motility of RAW 264.7 cells, which was rescued by transfection of Gα(i2) but not Gα(i3). These results indicate that Gα(i2), albeit redundant to Gα(i3) in some macrophage activation processes, clearly exhibits a Gα(i) isoform-specific role in the regulation of macrophage migration.

This paper presents an anthropometric database of high school and university students from Kuala Lumpur, Malaysia. Forty-one high school participants (21 males and 20 females), 13-17 years old, and 143 university students (74 males and 69 females) took part in the study. Twenty-one static body dimensions were measured. The greatest mean differences in the anthropometric data between male and female high school students were found in the sitting elbow height. In addition, a comparison of anthropometric data of male and female university students showed that data for males and females were significantly different, except for buttock-popliteal length, sitting elbow height and thigh clearance. The primary aim of this study was to develop an anthropometric database that could be used as a primary reference in designing products, devices and equipment for ergonomic learning environments.

Purpose: To estimate the predictive accuracy and clinical usefulness of the Chedoke-McMaster Stroke Assessment (CMSA) predictive equations., Method: A longitudinal prognostic study using historical data obtained from 104 patients admitted post cerebrovascular accident was undertaken. Data were abstracted for all patients undergoing rehabilitation post stroke who also had documented admission and discharge CMSA scores. Published predictive equations were used to determine predicted outcomes. To determine the accuracy and clinical usefulness of the predictive model, shrinkage coefficients and predictions with 95% confidence bands were calculated., Results: Complete data were available for 74 patients with a mean age of 65.3±12.4 years. The shrinkage values for the six Impairment Inventory (II) dimensions varied from -0.05 to 0.09; the shrinkage value for the Activity Inventory (AI) was 0.21. The error associated with predictive values was greater than ±1.5 stages for the II dimensions and greater than ±24 points for the AI., Conclusions: This study shows that the large error associated with the predictions (as defined by the confidence band) for the CMSA II and AI limits their clinical usefulness as a predictive measure. Further research to establish predictive models using alternative statistical procedures is warranted.

Background: Fat intake has been shown to play a role in the etiology of breast cancer, but the findings have been inconsistent., Objective: To assess the association of premenopausal and postmenopausal breast cancer risk with fat and fat subtypes intake., Methodology: This is a population based case-control study conducted in Kuala Lumpur, Malaysia from January 2006 to December 2007. Food intake pattern was collected from 382 breast cancer patients and 382 control group via an interviewer-administered food frequency questionnaire. Logistic regression was used to compute odds ratios (OR) with 95% confidence intervals (CI) and a broad range of potential confounders was included in analysis., Results: This study showed that both premenopausal and postmenopausal breast cancer risk did not increase significantly with greater intake of total fat [quartile (Q) 4 versus Q1 OR=0.76, 95% CI, 0.23-2.45 and OR=1.36, 95% CI, 0.30-3.12], saturated fat (ORQ4 to Q1=1.43, 95% CI, 0.51-3.98 and ORQ4 to Q1=1.75, 95% CI, 0.62-3.40), monounsaturated fat (ORQ4 to Q1=0.96, 95% CI, 0.34-1.72 and ORQ4 to Q1=1.74, 95% CI, 0.22-2.79), polyunsaturated fat (ORQ4 to Q1=0.64, 95% CI, 0.23-1.73 and ORQ4 to Q1=0.74, 95% CI, 0.39-1.81), n-3 polyunsaturated fat (ORQ4 to Q1=1.10, 95% CI, 0.49-2.48 and ORQ4 to Q1=0.78, 95% CI, 0.28-2.18), n-6 polyunsaturated fat (ORQ4 to Q1=0.67, 95% CI, 0.24-1.84 and ORQ4 to Q1=0.71, 95% CI, 0.29-1.04) or energy intake (ORQ4 to Q1=1.52, 95% CI, 0.68-3.38 and ORQ4 to Q1=2.21, 95% CI, 0.93-3.36)., Conclusion: Total fat and fat subtypes were not associated with pre- and postmenopausal breast cancer risk after controlling for age, other breast cancer risk factors and energy intake. Despite the lack of association, the effects of total fat and fat subtypes intake during premenopausal years towards postmenopausal breast cancer risk still warrant investigation.

Background: A cross-sectional studywas carried out to determine the prevalence of complementary and alternative medicine (CAM) use by breast cancer survivors., Methods: A descriptivesurveydesignwasdeveloped. Information on sociodemographic characteristics, cancer clinical treatment history, and use of CAM were obtained through a modified self-administered questionnaire from 116 Malay breast cancer survivors aged 21 to 67 years who were 2 years postdiagnosis and currently undergoing follow-up treatment at breast cancer clinics at Hospital Kuala Lumpur and Universiti Kebangsaan Malaysia Medical Centre., Results: Data suggest that 64% of the participants were identified as CAM users; dietary supplements were the most common form used, followed by prayer and Malay traditional medicine. Within the wide range of dietary supplements, multivitamins were most often taken followed by spirulina, vitamin C, evening primrose oil, and herbal products. Contrary to other findings, the CAM users were found to be older, had secondary education levels, and were from middle-income households. However, there was no significant difference between CAM users and nonusers in this study. Family members played an important role as the main source of information along with doctors/health care providers, friends, and printed materials/mass media. The reasons participants gave for using CAM were mainly to assist in healing the body's inner strength, to cure cancer, and to reduce stress. Only half of the participants consulted with their physicians regarding the safety of CAM use. The participants began to use CAM while undergoing clinical treatments. Most of the participants used CAM for more than a year. About RM100 to RM149 (31.88 USD to 47.50 USD at press time) were spent monthly on CAM by 32% of the participants. The CAM use was found to be effective and beneficial for patients' disease states, and they were contented with the usage of the CAM therapies. Multivariate analysis revealed that thedecision to use or not to use CAM was not dependent on sociodemographic background or cancer clinical treatment history., Conclusions: CAM was commonly used by breast cancer survivors as a coping mechanism to battle the disease.

FcgammaRIV is a relatively new IgG Fc receptor (FcgammaR) that is reported to contribute to the pathogenesis of autoimmune diseases, although its specific role in relation to FcgammaRIII, complement and IgG2 subclasses remains uncertain. Here we define FcgammaRIV on macrophages as a receptor for soluble IgG2a/b complexes but not for cellular bound IgG2a and show that simultaneous activation of FcgammaRIV and FcgammaRIII is critical to mediate certain type II/III autoimmune responses. FcgammaRIII-deficient mice display compensatory enhanced FcgammaRIV expression, are protected from lung inflammation after deposition of IgG complexes, and show reduced sensitivity to IgG2a/b-mediated hemolytic anemia, indicating that increased FcgammaRIV alone is not sufficient to trigger these diseases in the absence of FcgammaRIII. Importantly, however, blockade of FcgammaRIV is also effective in inhibiting phagocytosis and cytokine production in IgG2b-induced anemia and acute lung injury, processes that display a further dependence on C5a anaphylatoxin receptor. Using gene deletion and functional inhibition studies, we found that FcgammaRIII and FcgammaRIV are each essential to trigger an FcRgamma-linker for activation of T-cell-dependent signal that drives C5a production in the Arthus reaction. Together, the results demonstrate a combined requirement for FcgammaRIII and FcgammaRIV in autoimmune injury, and identify the linker for activation of T cells adaptor as an integral component of linked FcgammaR and C5a anaphylatoxin receptor activation to generate inflammation.

Background: The metabolic syndrome (MetS) is a cluster of metabolic abnormalities comprising visceral obesity, dyslipidaemia and insulin resistance (IR). With the onset of IR, the expression of lipoprotein lipase (LPL), a key regulator of lipoprotein metabolism, is reduced. Increased activation of glucocorticoid receptors results in MetS symptoms and is thus speculated to have a role in the pathophysiology of the MetS. Glycyrrhizic acid (GA), the bioactive constituent of licorice roots (Glycyrrhiza glabra) inhibits 11beta-hydroxysteroid dehydrogenase type 1 that catalyzes the activation of glucocorticoids. Thus, oral administration of GA is postulated to ameliorate the MetS., Results: In this study, daily oral administration of 50 mg/kg of GA for one week led to significant increase in LPL expression in the quadriceps femoris (p < 0.05) but non-significant increase in the abdominal muscle, kidney, liver, heart and the subcutaneous and visceral adipose tissues (p > 0.05) of the GA-treated rats compared to the control. Decrease in adipocyte size (p > 0.05) in both the visceral and subcutaneous adipose tissue depots accompanies such selective induction of LPL expression. Consistent improvement in serum lipid parameters was also observed, with decrease in serum free fatty acid, triacylglycerol, total cholesterol and LDL-cholesterol but elevated HDL-cholesterol (p > 0.05). Histological analysis using tissue lipid staining with Oil Red O showed significant decrease in lipid deposition in the abdominal muscle and quadriceps femoris (p < 0.05) but non-significant decrease in the heart, kidney and liver (p > 0.05)., Conclusion: Results from this study may imply that GA could counteract the development of visceral obesity and improve dyslipidaemia via selective induction of tissue LPL expression and a positive shift in serum lipid parameters respectively, and retard the development of IR associated with tissue steatosis.

Fcgamma receptors (FcgammaRs) on mononuclear phagocytes trigger autoantibody and immune complex-induced diseases through coupling the self-reactive immunoglobulin G (IgG) response to innate effector pathways, such as phagocytosis, and the recruitment of inflammatory cells. FcRgamma-based activation is critical in the pathogenesis of these diseases, although the contribution of FcgammaR-mediated calcium signaling in autoimmune injury is unclear. Here we show that macrophages lacking the endoplasmic reticulum-resident calcium sensor, STIM1, cannot activate FcgammaR-induced Ca(2+) entry and phagocytosis. As a direct consequence, STIM1 deficiency results in resistance to experimental immune thrombocytopenia and anaphylaxis, autoimmune hemolytic anemia, and acute pneumonitis. These results establish STIM1 as a novel and essential component of FcgammaR activation and also indicate that inhibition of STIM1-dependent signaling might become a new strategy to prevent or treat IgG-dependent immunologic diseases.